Researchers of the The University of California (USA) has identified a series of biomarkers – genes and specific brain circuits in mice – associated with a common symptom of depression: lack of motivation.
The finding, which is published in the journal «Neuron», could be used to find new ways to diagnose and potentially treat people suffering from lack of motivation and to bring the day of precision medicine to psychiatric disorders such as depression.
In patients with depression the symptoms may differ greatly. Precisely this lack of a connection between symptoms and treatments is a main reason why, approximately, half of people with depression do not respond to medication or other therapies, and the side effects of these medications are common.
"If we had a biological marker for specific symptoms of depression, we could simply do a blood test or take pictures of the brain and then identify the appropriate medication for that patient," says Stephan Lammel, assistant professor of molecular and cellular biology at UC Berkeley. That would be the ideal case, but we are far from that situation right now.
Now, for the first time, Lammel and his team have identified genes in a region of the brain, the lateral habenula, which are overactivated in mice that show reduced motivation as a result of chronic stress. This region of the brain in mice is not associated with other symptoms of depression, such as anxiety and anhedonia, the inability to feel pleasure.
«We believe that our study not only has the potential to transform the way basic scientists study depression in animals, but that the combination of anatomical, physiological and molecular biomarkers described could lay the groundwork to guide the development of the next generation of antidepressants that are designed for specific symptoms of depression, ”says Lammel.
Lammel and Ignas Cerniauskas, a UC Berkeley student, work on models of depression in mice that have been a pillar of basic research on this disorder for the past 60 years. Putting mice under constant stress produces at least three common symptoms of human depression: anxiety, lack of motivation and loss of pleasure, which scientists study to try to understand in humans.
“Unfortunately, the treatment of depression is often based on conjecture. No treatment works for everyone, and no one has objective data on how to differentiate the enormous variability of symptoms and subtypes of depression – Lammel laments. If we specifically understand how the brain changes in those animals with a certain type of symptom, there may be a way to specifically reverse these symptoms.
In response to a small recent clinical study in which physicians electrically stimulated the lateral habenula and found an improvement in symptoms in depressed patients who were resistant to other therapies, Lammel and Cerniauskas decided to investigate that area of the brain.
The lateral habenula It has received increasing attention in recent years, partly because it is connected to the dopamine and serotonin systems in the brain, and it is known that both are involved in depression. The most common medications currently used to treat depression are serotonin reuptake inhibitors (IRS) such as 'Zoloft' and 'Prozac'.
«After chronic stress, there is an increase in the neural activity of the lateral habenula cells (they trigger more, they become hyperactive) and we discovered that this hyperactivity was only present in mice that showed very strong deficits in motivated behavior, but not in animals that showed anxiety or animals that showed anhedonia, ”says Lammel.
Subsequently, his team identified the specific synapses, cells and circuits in the lateral habenula that are altered by chronic stress in these particular mice, and in collaboration with Csaba Földy and his colleagues in the University of Zurich, they also found genes that are overexpressed.
Lammel and Cerniauskas are currently working with Földy's laboratory using CRISPR-Cas9 to interfere or completely eliminate these genes to determine which are critical for the hyperactivity of the lateral habenula cells that cause lack of motivation.
This could lead to medications that interfere with these pathways, reduce the activity of the cells in the lateral habenula and increase motivation. They also plan to look for biomarkers of other symptoms of depression, such as anxiety and anhedonia.
«Our strategy is to stop considering depression as a single or homogeneous disease. Many doctors already see depression in this way, which shows that it is essential to have collaboration between basic and clinical researchers, ”concludes Lammel.
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